Children with disseminated neuroblastoma have a very high risk of treatment failure and death despite receiving intensified chemotherapy, radiation therapy and immunotherapy. The long-term goal of our laboratory is to substantively improve neuroblastoma cure rates by developing patient-specific therapies that target the unique oncogenic drivers of each case. Within the context of the Pediatric Preclinical Testing Consortium (PPTC) we propose a Neuroblastoma Research Program built on richly annotated and highly characterized patient derived xenograft (PDX) and other murine models. The central hypothesis to be tested in this Program is that oncogenic drivers of neuroblastoma can be defined and exploited through rationally designed combinatorial therapies based on validated and clinically measurable biomarkers. Through our dedicated focus on neuroblastoma and our central role in the former Pediatric Preclinical Testing Program, we have developed an investigative team, and rich set of resources and reagents, to be uniquely positioned to achieve the goals of the Program and the PPTC. Here we propose to use a large (and growing) collection of PDX models that have been fully characterized with the most modern genomic technologies to address three specific research aims. First, we will seek to exploit our recent discovery that high-risk neuroblastoma frequently harbor activating mutations in ALK or downstream components of the MAPK signaling pathway at the time of disease relapse. Here we will develop combinatorial therapies that not only directly target the pathway, but also a major bypass mechanism of resistance by simultaneously inhibiting the PI3K-AKT pathway. Second, we will seek to target the MYCN oncoprotein, the most well characterized oncogenic driver in high-risk neuroblastoma, via combined therapy of a bromodomain and extra-terminal repeat inhibitor with an inhibitor of the MAPK pathway. Third, we will seek to take advantage of the fact that inactivating mutations in major tumor suppressor genes such as TP53 and RB1 are rare in neuroblastoma, and that therapeutic strategies to trap these proteins in the nucleus will synergistically enhance cell death caused by DNA damaging agents. These exemplar Aims provide a roadmap for an evidence-based and hypothesis-driven research Program that will be positioned to pursue up to 10 research aims (preclinical therapeutic trials) annually through priorities set by the PPTC steering committee. The Neuroblastoma Research Program within the PPTC will deliver on the promise of biomarker-directed therapeutics in cancer by performing the pivotal preclinical studies that will greatly enhance our ability to design early phase clinica trials enriched for patients with high potential to benefit. Thus, this Program will seek to shift he paradigm for how high-risk neuroblastoma patients are treated with the goal of substantively improving the outcomes, both in terms of cure rates, but also by decreasing the toxicity associated with current standards of care.